Uncommon Terpenoids from Salvia Species: Chemistry, Biosynthesis and Biological Activities

The search for new bioactive compounds from plant sources has been and continues to be one of the most important fields of research in drug discovery. However, Natural Products research has continuously evolved, and more and more has gained a multidisciplinary character. Despite new developments of methodologies and concepts, one intriguing aspect still persists, i.e., different species belonging to the same genus can produce different secondary metabolites, whereas taxonomically different genera can produce the same compounds. The genus Salvia L. (Family Lamiaceae) comprises myriad distinct medicinal herbs used in traditional medicine worldwide that show different pharmacological activities due to the presence of a variety of interesting specialized metabolites, including mono-, sesqui-, di-, sester-, tri-, tetra-, and higher terpenoids as well as phenylpropanoids, phenolic acid derivatives, lignans, flavonoids, and alkaloids. We herein summarize the research progress on some uncommon terpenoids, isolated from members of the genus Salvia, which are well recognized for their potential pharmacological activities. This review also provides a current knowledge on the biosynthesis and occurrence of some interesting phytochemicals from Salvia species, viz. C23-terpenoids, sesterterpenoids (C25), dammarane triterpenoids (C30), and uncommon triterpenoids (C20+C10). The study was carried out by searching various scientific databases, including Elsevier, ACS publications, Taylor and Francis, Wiley Online Library, MDPI, Springer, Thieme, and ProQuest. Therefore, 106 uncommon terpenoids were identified and summarized. Some of these compounds possessed a variety of pharmacological properties, such as antibacterial, antiviral, antiparasitic, cytotoxic and tubulin tyrosine ligase inhibitory activities. Due to the lack of pharmacological information for the presented compounds gathered from previous studies, biological investigation of these compounds should be reinvestigated.


Sesterterpenoids
Sesterterpenes (C 25 ) are a class of terpenoid compounds that have been frequently reported from bacteria, fungi, lichens, insects, marine invertebrates (particularly marine sponges), and some higher plant families such as Asteraceae, Lamiaceae, Lobariaceae, Gentianaceae, and Pteridaceae. Sesterterpenoids are among the most interesting classes of specialized metabolites since they possess relevant biological and pharmacological activities [50]. Sesterterpenoids reported from plants of the genus Salvia possess a prenyllabdane skeleton ( Figure 4) [51], all containing a γ-lactone ring. Accordingly, these specialized metabolites are divided into three different subgroups.

Bicyclic Sesterterpenoids
A literature search on Salvia plants revealed that only eight species biosynthesize γ-lactone-containing bicyclic sesterterpenes. They are S. hypoleuca, S. syriaca, S. sahendica, S. mirzayanii, S. palaestina, S. lachnocalyx, S. dominica and S. tingitana, half of which are endemic to Iran. A plausible biosynthetic pathway is shown in Figure 5. As an example of this type of sesterterpenes, we can infer the following specialized metabolites with the increasing oxidation state of C-23 from CH 3 to CH 2 OH, CHO, COOH, COOMe and the lactone ring between C-6 and C-23.
Investigation of the Arabidopsis genome revealed that the putative sesterterpene gene clusters consist of geranylfarnesyl diphosphate synthase (GFPPS), terpene synthase (TPS), and cytochrome P450s. Therefore, the functional identification of GFPPS-sesterTPS-P450 gene clusters of Arabidopsis in vitro, and subsequent detection of sesquiterpenes in planta were achieved. Furthermore, subcellular localization of identified enzymes involved in sesterterpene biosynthesis suggested that sesterterpenes (GFPPSs and sesterTPSs) are produced from the plastidial 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway. Due to the presence of GFPPS-TPS-P450 clusters in the Arabidopsis genome, the TPSs located in these biosynthetic gene clusters were investigated to verify if they utilize GFPP as a substrate to produce sesterterpene backbones (even though no sesterterpene has been reported previously in Arabidopsis). By using different expression systems, 18 Brassicaceaespecific sesterTPSs were characterized, and 20 sesterterpene products were purified and elucidated. Moreover, phylogenetic analysis of plant TPS sequences clearly showed that functional sesterTPSs evolved from the TPS-a subfamily, the members of which always utilize GPP and/or FPP as substrates. However, since plant sesterTPSs have been identified only from Brassicaceae, it is still unclear whether the sesterTPSs from other plant species, such as Lamiaceae, evolved from the TPS-a subfamily or from other TPS subfamilies [50].
Based on this finding, 9 is hypothesized to be generated by allylic hydroxylation at C-16 of the side chain of the bicyclic sesterterpene skeleton formed by cyclization of GFPP. Oxidation of the hydroxyl group at C-19 gives the intermediate I, which undergoes lactonization between OH-16 and the carboxylic acid at C-19 to give II. The intermediate II can proceed in two directions. First, hydroxylation at C-6 and C-15 leads to the formation of 11. On the other hand, hydroxylation at C-15 and epoxidation of the double bond between C-13 and C-14 produces III. Hydrolysis of the 13,14-epoxide and dehydration of OH-15 in III gives rise to 10 ( Figure 5).

Bicyclic Sesterterpene Lactones Containing C-23 Carboxylic Acid
Salvimirzacolide (27) (Figure 8), a bicyclic sesterterpene lactone whose C-23 possesses a carboxylic acid function, was isolated from the MeOH-soluble portion of an acetone extract of the aerial parts of S. mirzayanii Rech. and Esfandieri, collected from Malek and Adori villages near Kerman, Iran. Extensive NMR spectral analysis, in combination with X-ray analysis, revealed that 27 is a normal bicyclic sesterterpene (with 10R configuration) containing a γ-butyrolactone ring with the R-configuration at C-16 [57]. In 1982, Rustaiyan et al. first described the isolation of a bicyclic sesterterpene lactone with a methyl ester of carboxylic acid at C-23 and named it salvileucolide methyl ester (33) ( Figure 9) from a diethyl ether extract of the aerial parts of S. hypoleuca Benth, collected from the north of Teheran, Iran [58]. Later, Rustaiyan and Sadjadi also reported the isolation of 33 ( Figure 6) from a MeOH-soluble fraction of S. syriaca L., collected from north of Taleghan, Iran [55]. Moghaddam et al. also reported the isolation of 33 from the aerial parts of S. sahendica Boiss & Buhse, an endemic plant of Iran which was collected in Bostanabad, East of Tabriz. However, neither the relative nor absolute configuration of C-16 in 33 was determined [59]. Only in 1996 did Linden et al. [60] succeed in determining the absolute configuration of the stereogenic carbons in 33 by performing an X-ray analysis of 6-O-pbromobenzoyl ester of 33 (33"; Figure 9), whose ORTEP diagram putatively indicated the R-configuration at C-10 and C-16 [60]. Furthermore, salvileucolide methyl ester (SME) derivatives, viz. 14-hydroperoxy-13(21)-dehydro-SME (34), 13-hydroperoxy-14-ene-SME (35), 13-epi-hydroperoxy-14-ene-SME (36), and 14,17-cycloperoxy-13(21)-dehydro-SME (37) (Figure 9), were also isolated from the polar fraction of the aerial parts of S. hypoleuca. The structures of 34-37 were established by NMR spectral analysis [61]. and 40, which were consistent with a β-orientation of Me-22, Me-24, and Me-25 as well as a trans junction of the decalin ring system. Additionally, the absolute configuration of C-15 was determined as S by the Mosher's method. Moreover, the vibrational circular dichroism (VCD) spectra of 39 and 40 were recorded and compared to their calculated spectra at the B3LYP/6-31+G(d,p) level of theory. It was found that the experimental and calculated VCD spectra showed a significantly better fit for the (4R, 5R, 8R, 9R, 10S, 16R)-39. On the other hand, the VCD similarity analysis gave no clear preference to any of the four calculated spectra for 40 [52].
3.1.6. Bicyclic Sesterterpenes Containing C-6, 23-and C-16, 19-Diolide Salvileucolide-6,23-lactone (41) (Figure 10), the first 6,23-lactone-containing sesterterpene reported from Salvia plants, was isolated from the diethyl ether extract of the aerial parts of S. hypoleuca Benth. Like 33, the structure of 41 and the stereochemistry at C-5 and C-6 were established based on the observation of the 1 H NMR spectrum through spin decoupling and the addition of the chemical shift reagent, Eu(fod) 3 , and the 13 C NMR spectrum. However, the relative and absolute configurations of C-16 were not determined [58].  Lachnocalyxolide B (47) (Figure 10) was isolated from a defatted acetone extract of the aerial parts of S. lachnocalyx Hedge, collected from Eghlid in the Fars Province, Iran. The structure of 47 was established by 1D and 2D NMR spectral analysis and HR-ESIMS data. The relative configuration of 47 was established based on NOESY correlations from H-6β to H 3 -22, H 3 -24, H 3 -25, and H-7β, as well as from H-5α to H-9α. However, the relative configurations at C-14 and C-16 were not assigned because of high conformational flexibility and free rotation around C-14/C-15 and C-15/C-16 [62].
A further sesterterpene diolide, 8α-hydroxy-13-hydroperoxylabd-14,17-dien-19,16;23,26αdiolide (50) (Figure 10), was isolated from the acetone extract of the aerial parts of S. sahendica, collected between Tabriz and Bostanabad, East Azerbaijan Province, Iran. The structure of 50 was elucidated by detailed analysis of 1D and 2D NMR experiments and HRESIMS. The relative configuration of the lactonized C-6 was determined as α, based on the coupling constant of H-6 with H-5 (J 5,6 = 11 Hz) as well as by NOESY correlations from H-6 to H 3 -22, H 3 -24 and H 3 -25, all of which are β-oriented. Moreover, H-5 and H-9 also showed a NOESY correlation, implying a β-orientation of the side chain on C-9. However, the configurations of C-13 and C-16 were not determined [63].  (Figure 12). The relative configurations at C-4, C-5, C-6, C-9, and C-10 of 57, 58 and 59 were established based on the coupling constants of H-5, H-6, and H-9 as well as by NOESY correlations from H-6 to H 3 -22, H 3 -24, and H 3 -25, and from H-5 to H-9. By using a modified Mosher's method, the configuration of C-15 in 59 was assigned as 15S. Tentative assignment of the absolute configurations of C-15 and C-16 by comparison of the calculated and experimental VCD spectra was unsuccessful since the results were in conflict with that obtained from the Mosher's method. Therefore, the absolute configuration of C-16 in 57 and 59 was assigned by comparison of the NMR data with those reported for the congeners [52].
Hasan et al. isolated salvidominicolide B (60) (Figure 12) from the aqueous MeOH portion of the CHCl 3 extract of whole parts of S. dominica L., which was collected in Al-Mastaba region, Jordan. The structure of 60 was established by detailed analysis of 1D and 2D NMR spectra and HRMS data [64].

Tricyclic Sesterterpenoids
So far, 21 tricyclic sesterterpenoids containing a tetrahydropyran ring, angularly fused with a decalin ring system, have been reported from six Salvia species viz. S. aethiopis, S. dominica, S. yosgadensis, S. tingitana, S. lachnocalyx, and S. mirzayanii. Like bicyclic sesterterpenoids, this group of sesterterpenoids is categorized as C-23 methyl, C-23 carboxylic acid, C-23 carboxylic acid methyl ester, C-23,6 and C-16,19 diolides. The biosynthetic pathway of these compounds could originate from 8, 16-dihydroxy bicyclic sesterterpene containing γ-lactone, 11, followed by nucleophilic addition of OH-8 to C-13 of the double bond with concomitant elimination OH-15 of the side chain to give VI. Epoxidation of VI gives VII, which upon hydroxylation of the C-14/C-15-epoxide gives VIII. Elimination of OH-15 by dehydration leads to a formation of 63. Nucleophilic addition of the double bond at C-16 by H 2 O would give IX, which after dehydration generates a double bond between C-14 and 15 and a hemiacetal function at C-16 in 64 ( Figure 13).
Two γ-methoxybutenolide-containing sesterterpenes, 13-epi-salviaethiopisolide (61 and 61 ) together with salviaethiopisolide (62 and 62 ) (Figure 14), were isolated from the MeOH extract of the aerial parts of S. aethiopis, collected in Spain. The 1 H and 13 C NMR spectra of both compounds displayed a duplicity of several signals, with a relative intensity of 55/45, suggesting that the compounds were a mixture of two epimers. The structures of both compounds were elucidated by 1D and 2D NMR spectral analysis as well as chemical transformation. Analysis of the NMR data of the acetylation and reduction products confirmed that both compounds were epimeric at C- 16  → π* transition) and a negative CE at 235 nm (π → π* transition of α, β-unsaturated-γ-butenolide). The calculated ECD spectrum of the (4R, 5R, 8R, 9R, 10S, 13R)-stereoisomer showed a strong positive CE at 290 nm that fitted well with the experimental data. However, the negative CE at 230 nm in the experimental spectrum was absent in the calculated spectrum. Therefore, the ECD spectrum for the (4R, 5R, 8R, 9R, 10S, 13S)-stereoisomer was calculated but showed a negative CE at 290 nm. Therefore, the optical rotations for both stereoisomers were also calculated and compared with the experimental data to confirm the absolute configuration, thus establishing the structure of 72 as (4R,5R,8R,9R,10S,13R)-manoyloxide-15,17-dien-15(Z)-16,19-olide [68].
A manoyloxide-type sesterterpene with a furan-containing side chain and a carboxylic acid ester function at C-23, (14E)-methylmanoyloside-14,16,18-trien-16,19-oxide-23-carboxilate (73) (Figure 14), was also isolated from the n-hexane-insoluble fraction of the CH 2 Cl 2 extract of the aerial parts of S. tingitana. The structure of 73 was elucidated by extensive analysis of 1D and 2D NMR spectra and HR-ESIMS data. The NOESY correlations from H 3 -22 to H 3 -24, H 3 -25 and from H-5 to H-9 indicated that the relative configuration of 73 was the same as that of the previously reported manoyloxide-type sesterterpenoids. However, the relative configuration of C-13 remained unassigned due to overlapping signals of H 3 -21 and H 3 -22 [52].
Lachnocalyxolides A (74) and C (75) (Figure 14) were isolated from the ethyl acetate (EtOAc)-soluble fraction of the acetone extract of the aerial parts of S. lachnocalyx Hedge, collected in Iran. Like some previously discussed manoyloxide-type sesterterpenes, the 1 H NMR spectrum of 74 showed two pairs of signals of H-14 and H-15 while the 13 C NMR spectrum exhibited two pairs of the carbon signals of the two double bonds (C-15/C-16 and C-17/C-18) and one pair of a carbinol proton (C-14), indicating the presence of an epimeric pair (74 and 74 ; Figure 14). Compound 75 was elucidated as a manoyloxide-type sesterterpene 6,23-olide with a hydroxyl group on C-14 and an α,β-unsaturated-γ-lactone in the side chain by 1 H and 13 C NMR data. The relative configuration of 75 was corroborated by NOESY correlations from H-6β to H 3 -22, H 3 -24, H 3 -25, and H-7β, as well as from H 3 -22 to H 3 -21, confirming that they are cofacial. Since diagnostic NOESY correlations were observed from H-14 to H 3 -21, H-12β, and H-12α, the predominant conformation of 75 is the one having gauche interactions of H-14 with both C-21 and C-12, indicating the configuration of the hydroxyl group on C-14 [62].
Hasan et al. reported the isolations of salvidominicolide A (76), a manoyloxide-type sesterterpene with 6,23-pyran moiety and a side chain containing α, β-unsaturated-γlactone ( Figure 14) from S. dominica L. The structure of 76 was elucidated by 1D and 2D NMR spectral analysis and HRMS data. However, the stereochemistry of C-15 was not determined [64].

Norsesterterpenes
The n-hexane-insoluble portion of the CH 2 Cl 2 extract of the aerial parts of S. tingitana also furnished a C-23 norsesterterpene (77) (Figure 15) whose planar structure was established by 1D and 2D NMR spectral analysis and HRMS data. The NOESY correlations from H-6 to H 3 -22, H 3 -24, and H 3 -25, and from H-5 to H-9 indicated a trans-junction of the decalin ring system and a β-orientation of H-6 and Me-24. However, the stereochemistry of C-16 of the lactone ring was not determined. Consequently, the structure of 77 was established as (13E)-4α,6α,8α-trihydroxy-labd-13 (14),17(18)-dien-16,19-olide. It is noteworthy mentioning that 77 is the first C-23 norsesterterpene from a Salvia species [52]. In a continuing investigation of Turkish Salvia species, Topcu et al. reported the isolation of dinorsesterterpenes, yosgadensonol (78) and 13-epi-yosgadensonol (79) (Figure 15) from the acetone extract of the aerial parts of S. yosgadensis, collected from Central Turkey (near Sultanhani, Konya). The structures of 78 and 79 were elucidated by HREIMS, 1D and 2D-NMR spectral analysis. The 1D and 2D NMR spectra and the molecular formula of both compounds (C 23 H 38 O 3 ) identified them as 19,20-dinorsesterterpenes possessing the same tricyclic ring system as those of manoyloxide-type sesterterpenes but differ in the stereochemistry of C-13. The stereochemistry of C-16 in both compounds was determined by observing the NOE effects of Me-21 and Me-25 signals upon irradiation of Me-22 [69].
Another two dinorsesterterpenes, 6-dehydroxy-yosgadensonol (80) and 6-dehydroxy-13-epi-yosgadensonol (81) (Figure 15), were reported form the acetone extract of the aerial parts of S. limbata C. A. Meyer. The structures of the compounds were elucidated by interpretation of the 1 H and 13 C NMR spectra and comparison of their NMR data with those of 78. The structure of 81 was established based on the slightly different proton chemical shift values of Me-21, Me-22 and Me-25 [70].
A C-17, C-18, C-19, and C-20 tetranorsesterterpene, (17,18,19,20-tetranor-13-epi-manoyloxide-14-en-16-oic acid-23,6α-olide; 82) ( Figure 15), was also isolated from the acetone extract of the aerial parts of S. sahendica. The structure of 82 was elucidated by HRESIMS and 1D and 2D NMR spectral analysis. The relative configuration at C-6 of the 23,6-lactone was determined as R on the basis of the magnitude of the coupling constants of H-6 as well as NOESY correlations from H-6 to H 3 -22, H 3 -24, and H 3 -25, all β-oriented. On the other hand, Me-21 was established as α-oriented due to a lack of NOE enhancement upon irradiation of Me-22. It is important to note that 82 is the first tetranorsesterterpene to have been reported from the genus Salvia [63].

Dammarane Triterpenoids
Dammarane-type triterpenoids are tetracyclic triterpenoids whose structural feature is characterized by a 6/6/6/5 ring system with H-5α, H-9α, H-13β, three β-CH 3 groups on C-4 (CH 3 -28), C-8 (CH 3 -20), C-10 (CH 3 -19), one α-CH 3 group on C-14 (CH 3 -30), C-17β-side chain, and 20R or S configuration ( Figure 16 (Figure 17) were isolated from the acetone extract of the aerial parts of S. hierosolymitana Boiss., which was collected from the botanic garden of Palermo, Italy. The structures of both compounds were elucidated by electron impact mass spectrometry (EIMS) and analysis of 1 H and 13 C NMR spectra. By analysis of the 13 C NMR data, it was impossible to deduce the absolute configurations of the stereogenic carbons of the pyran ring in the side chain of 84 as (20S, 24R) or (20R, 24S). However, the configurations of these carbons were conclusively determined as (20S, 24R) by a single-crystal X-ray crystallography of the 25, 26, 27-trinor-γ-lactone derivative, a degradation products of 84 with Jones' reagent [73]. Kolak et al. [74] reported the isolation of pixynol [(20S,24R)-epoxydammarane-3β,12β,25triol] (85) (Figure 17) from the acetone extract of roots of S. barrelieri Ettling, an endemic Salvia species to Algeria collected from Ammoucha-Setif district in Northeastern Algeria. Although 85 was first reported from a lichen Pyxine endochrysina NYL. [75], and later from the acetone extract of roots of S. bicolor, collected in Malaga, Spain [76], the absolute configurations of C-20 and C-24 had not been determined. However, Kolak et al. [74] were able to obtain a suitable crystal of 85 for X-ray analysis and have assigned a complete stereochemistry of 85.
In addition to 85, Valverde et al. also isolated (20S, 24R)-epoxydammar-12β, 25-diol-3-one (86) (Figure 17) from the acetone extract of roots of S. bicolor. The β-orientation of the hydroxyl group on C-12 was proposed by two large axial-axial coupling constants (ca. 10.4 Hz) of H-12 with H-13 and H-11β while the absolute configurations of C-20 and C-24 were assigned by 13 C chemical shift values as well as comparison of the 13 C chemical shift values with those of the model compound [76].
Esquivel et al. [78] reported the isolation of the undescribed trinordammarane triterpene, amblyol (90) and the previously reported amblyone (91) [79] (Figure 18) from the acetone extract of the aerial parts of S. aspera, collected in the state of Plueba, Mexico. Compound 90 was isolated as a C-24 epimeric mixture as revealed by duplicate signals for most of the carbons in the 13 C NMR spectrum. This hypothesis was corroborated by treatment of 90 with Jones reagent to give 91, as well as acetylation of 90 with Ac 2 O/pyridine in the presence of 4-dimethylaminopyridine to give two OAc-19. Finally, the stereostructure of one epimer was obtained by single-crystal X-ray crystallography.    Figure 20) were established by extensive analysis of 1D and 2D NMR spectra and were confirmed by single-crystal X-ray diffraction analysis [81]. Furthermore, the same research group has also reported the isolation of another triterpene of the same carbon skeleton, named salvadiol (97) (Figure 20) from the n-hexane soluble fraction of the same plant and whose structure was established by 1D and 2D NMR spectral analysis and single-crystal X-ray diffraction. The authors have proposed a biosynthetic pathway for 97 through a Diels-Alder type reaction of icetexone diterpene precursor with X, which was derived from an autoxidation of the monoterpene myrcene ( Figure 21) [82].    Further examination of the n-hexane extract of the aerial parts of S. hydrangea by the same research group led to the isolation of hydrangenone (100) (Figure 24), another heptacyclic triterpenoid with a 6/7/6/5/5 ring system similar to that of 98 and 99. The structure of 100 was elucidated by extensive analysis of 1D and 2D spectra. The relative configuration of 100 was established by NOESY correlations as well as by single-crystal Xray analysis while the absolute structure was established as 5S,8R,9R,10S,11R,22R,23R,25R by comparison of the experimental and calculated ECD spectra [84]. Continuation of a phytochemical investigation of the n-hexane extract of the aerial parts of S. hydrangea allowed Tabefam et al. to isolate further six unreported triterpenoids with rare skeleton, named hydrangenone B (101), pervoskones C-F (102-105) and salvadione D (106) (Figure 24), in addition to 95 (Figure 20). The structures of the isolated compounds were elucidated by comprehensive analysis of 1D and 2D NMR spectra and HRMS data. The absolute structures of all the compounds were determined by comparison of the calculated and experimental ECD spectra. In the case of 95, the absolute configurations of the stereogenic carbons were determined by single-crystal X-ray diffraction analysis using CuKα radiation. As a result, the absolute configurations of C-5, C-8, C-9, C-10, C-11,  It is interesting to note that since this group of C 30 -terpenes is proposed to derive from the Diel-Alder reaction between icetexone-type diterpenoid and an autoxidation product of myrcene (a monoterpene), they are sometimes referred to as "isoprenoids" to distinguish them from normal triterpenoids, which are formed by direct cyclization of 2,3-oxidosqualene.

Antiviral Activity
Since some 1,3-diketone-containing secondary metabolites are known as HIV-1 integrase inhibitors [87], Xu et al. tested 7 and 8 ( Figure 3) for their cytopathic effects against HIV-1. Compound 7 displayed better anti-HIV-1 activity than 8, with half-maximal effective concentration (EC 50 ) values of 40.74 and 89.13 µg/mL, respectively (selectivity index; SI of 2.19 and 1.78, respectively). Interestingly, it was found that the more carbonyl groups the compounds have the weaker anti-HIV-1 effects the compounds exhibit [48].
A series of sesterterpenes, viz. 11 ( Figure 5) (in 38, 68,  69, and 71), and 23,6α-γ-lactone ring (in 30 and 70) obviously decreased the affinity for the enzyme, but a C-13/C-14 double bond and C-15 methylene group were essential for the activity. Furthermore, treatment of MCF-7 (human breast cancer) cells with the most active compound, 31 (with KD of 4.7 × 10 −8 M from SPR assays) at a concentration of 100 µM for 24 and 48 h and then analyzed by Western blot ∆-2 tubulin levels, showed that 31 significantly penetrated the membrane and inhibited TTL inside the cancer cell. Thus, 31 could be considered a good lead for further drug developments to design a better drug because of its 10-fold higher activity than other compounds [54,56].

Antiparasitic Activity
Antiplasmodial activity-guided fractionation of S. hydrangea by n-hexane, EtOAc, and MeOH, revealed that the n-hexane fraction was active against Plasmodium falciparum K1 and Trypanosoma brucei rhodesiense STIB900, with IC 50 values of 3.2 and 18 µg/mL, respectively. Among the isolated compounds from this active fraction, 98 and 99 ( Figure 22  were active against Gram-positive bacteria, belonging to the Staphylococcus and Enterococcus genera. Compounds 33 and 41 were also found to inhibit the ATP production in purified mammalian rod outer segments, which is associated directly or indirectly with various human diseases [52]. In order to facilitate readers to quickly localize biological and pharmacological activities of these uncommon terpenoid compounds from the genus Salvia, the class of compounds (including compound names and numbers), plant sources, part used and biological/pharmacological activities are summarized in Table 1.

Conclusions and Future Perspectives
The outlined examples highlight that plants of the genus Salvia are an interesting source for compounds with novel and unique scaffolds for further development as drug leads. From the initial breakthrough, the structures of uncommon Salvia terpenoids, especially the dammarane-type triterpenoids and sesterterpenoids, have not been thoroughly investigated. Although this review covers 106 terpenoids from members of the genus Salvia and some proposed biosynthetic pathways, biological and pharmacological activities have been less considered due to the shortcoming in information regarding the biological properties obtained from previous studies. The biosynthetic pathways for apiananes, hassananes, and dammaranes indicate that secondary metabolite production can be species-specific. Owing to huge potential of underexplored bioactivities, terpenoids from Salvia species can certainly be explored as a promising group of secondary metabolites for applications in the pharmaceutical, cosmeceutical and agro industries. On the other hand, due to a lack of reliable technology, the relative and absolute configurations of many terpenoids studies in the 1970s and 1980s are still undetermined and can be a challenging task for researchers in this field. Therefore, a revisit of the stereochemistry of these compounds by modern chiroptical methods is another important aspect to be addressed. All in all, this review can provide an insight for researchers who look for bioactive secondary metabolites from Salvia plants with unique and rare scaffolds. Funding: This work is partially supported by national funds through FCT-Foundation for Science and Technology with the scope of UIDB/04423/2020 and UIDP/04423/2020.

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